Voltage-gated sodium channels play a central role in initiating and propagating action potentials in electrically excitable cells, see for example Yu and Catterall, Genome Biology 4:207 (2003) and references therein. Voltage-gated sodium channels are multimeric complexes characterized by an Alpha-subunit which encompasses an ion-conducting aqueous pore, the site of the essential features of the channel, and at least one Beta-subunit that modifies the kinetics and voltage-dependence of the channel gating. These structures are ubiquitous in the central and peripheral nervous system and are believed to play a central role in initiation and propagation of electrical signals in the nervous system.
It has been shown in human patients as well as in animal models of neuropathic pain that damage to primary afferent sensory neurons may lead to neuroma formation and spontaneous activity, as well as evoked activity in response to normally innocuous stimuli. [Carter, G. T. and Galer, B. S., Advances in the Management of Neuropathic Pain, Physical Medicine and Rehabilitation Clinics of North America, 2001, 12(2): pp 447 to 459]. Injuries of the peripheral nervous system often result in neuropathic pain persisting long after an initial injury resolves. Examples of neuropathic pain include, for example, post herpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lower back pain, phantom limb pain, pain resulting from cancer and chemotherapy, chronic pelvic pain, complex regional pain syndrome and related neuralgias. The ectopic activity of normally silent sensory neurons is thought to contribute to the generation and maintenance of neuropathic pain, which is generally assumed to be associated with an increase in sodium channel activity in the injured nerve. [Baker, M. D. and Wood, J. N., Involvement of Na Channels in Pain Pathways, TRENDS is Pharmacological Sciences, 2001, 22(1): pp 27 to 31.
Nine different Alpha-subunits have been identified and characterized in mammalian voltage-gated sodium channels. These structures are designated Nav 1.X sodium channels (X=1 to 9) in accordance with currently accepted nomenclature practice, designating their ion selectivity (Na), the physiological regulator (‘v’, potential, i.e. voltage), and the gene subfamily encoding them (1.X), with the number designator X (1 to 9) being assigned for the alpha subunit present in the structure (see Aoldin et al., Neuron, 28:365-368 (2000)). Nav1.7 voltage-gated sodium ion channels (herein designated “Nav 1.7 channels” in some instances for convenience) are expressed primarily in sensory and sympathetic neurons. They are believed to play a role in nociception and in particular have a central role in inflammatory pain perception, (see Wood et al. J. Neurobiol. 61: pp 55-71 (2004) and Nassar et al., Proc. Nat. Acad. Sci. 101(34): pp 12706-12711 (2004)). Accordingly it is believed that identification and administration of agents which interact to block Nav 1.7 voltage-gated sodium ion channels represents a rational approach for providing treatment or therapy for nociception disorders stemming from dysfunction of Nav1.7 voltage-gated sodium ion channels (see Clare et al., Drug Discovery Today, 5: pp 506-520 (2000)).
Because voltage gated sodium ion channels are ubiquitous in the central and peripheral nervous system and conservation of structures in the various Alpha-subunits characterizing voltage-gated sodium ion channels implicates the potential for producing serious side effects when utilizing therapeutic agents that target blocking voltage-gated sodium ion channels, therapeutic agents suitable for use in addressing nociception disorders require specificity in their action, for example, low activity blocking Nav1.5 sodium ion channels (which channels are thought to be important in regulation of cardiac function) while displaying potent activity in blocking Nav1.7 sodium ion channels (which is believed to be central in providing therapy for inflammatory nociception and disorders arising from dysfunctional Nav 1.7 sodium ion channels). It will be appreciated that in general activity selectively targeting Nav 1.7 sodium ion channels while not significantly effecting other Nav1.X channels would be advantageous in developing therapeutics for such disorders.
Published international application no. WO09/012242 (the '242 publication) describes compounds having the structure of Formula PA:
wherein R* is a proton, alkyl or heteroalkyl, aryl, or heteroaryl group, Y is an aryl group or a 5 or 6 member-ring heteroaryl group, L is either not present or is a cyclic structure containing nitrogen or substituted with nitrogen, B is a cycloalkyl, heterocycloalkyl, aryl or heteroaryl moiety, and Z is a five or six-member ring heteroaryl moiety, and optionally R*, N, and Y form a cyclic structure which may be a heteroaryl moiety, for example, the compound of Formula PB:
wherein R1, Y, and Z are as defined for the compound of Formula PA, and wherein each X1 is independently N or unsaturated carbon optionally substituted with hydrogen, halogen, CN, OH, alkyl or substituted alkyl. These compounds are said to have activity as Nav 1.7 channel and Nav 1.3 channel blockers but are not shown to have selectivity as specific Nav 1.7 channel blockers.
Compounds having Nav1.7 activity described in published international applications WO 2010/079443 (the '443 publication) and related WO2012/004706, WO2012/004714, WO2012/064984, WO2013/064983, and WO2013/064984 have the structure of Formula PC:
wherein X1 is N or C—R3 (R3 is a wide number of substituents including halogen), R1 is a cycloalkyl, aryl or heteroaryl moiety and R2 is a heteroaryl moiety.
Examples of these compounds include compounds of Formula PD:
where RAH is an aryl or heteroaryl moiety and RFa is one or more of a wide variety of substituents, for example the hetero-substituted aryl compounds of Formula PE and Formula PF:
wherein RHB is a heterobicyclo moiety.
An additional example of these compounds are the heterocycloalkyl-substituted compounds of Formula PG:
wherein at least one of X1F and X2F are a heteroatom and the other is either a substituted carbon or CH, RAH is an aryl or heteroaryl moiety and RFa is one or more of a wide variety of substituents. These foregoing compounds are said to have affinity for Nav 1.7 sodium channels and modest or low affinity for Nav1.5 sodium channels, but do not offer much structural diversity.
Recently, compounds described in published international applications WO 2013/025883 WO2013/086229, and WO2013/134518, having the structure of Formula PH:
wherein one of R2a or R2b is an aryl or heteroaryl moiety and the other is —H or alkyl, X3 to X5 are ═N— or ═CR5— (where R5 is a wide range of compatible substituents), X1a-1d are ═N—, —NR4— (where R4 is H, alkyl, or a wide variety of other substituents compatible with N), or ═CR3— (R3 is a wide number of substituents, including, H, alkyl, aryl and heteroaryl) and wherein X1c may be absent, in which case X1b is CH. These compounds claim activity for Nav1.7 sodium ion channels and selectivity over Nav1.5 channels.
There remains a need for additional compounds having high potency and selectivity for Nav 1.7 sodium channels, have acceptable bioavailability properties, and that offer a variety of cores to facilitate rational development of therapeutic agents for use as selective Nav 1.7 sodium ion channel blockers.